Clear cell papillary renal cell tumour

• An indolent renal neoplasm of low-grade clear cells in tubular or tubulopapillary architecture with characteristic nuclear polarisation.
• Formerly clear cell papillary RCC, renamed “tumour” in WHO 2022 because no convincing metastasis or tumour death has been shown.
• Branching or elongated tubules, acini, cysts and delicate papillae.
• Low-grade nuclei aligned toward the lumen, away from the basement membrane.
• Classic phenotype: diffuse CK7 and cup-like CAIX; GATA3 and 34βE12 often positive.
• Generally lacks biallelic VHL inactivation and 3p loss.
• Sporadic or in end-stage kidney disease; ccRCC and other mimics must be excluded.

Diagnostic pearl: low-grade clear cells + apical nuclei + diffuse CK7 + basolateral cup-like CAIX is the characteristic combination.

Architecture

• Well circumscribed; tubules, acini, cysts and papillae, tubules often dominate.
• Elongated, branching ribbons; short or abortive papillae; possible pseudocapsule.

Cells

• Cuboidal to low columnar, optically clear cytoplasm, distinct borders.
• Small uniform nuclei, inconspicuous nucleoli.

Nuclear polarisation

• Nuclei displaced toward the lumen form a linear row away from the basement membrane, clearest in elongated tubules and cyst lining.
• Variable between regions.

Stroma

• Delicate fibrous or hyalinised; oedema, fibrosis or smooth muscle-rich areas may occur.

Diagnostic pearl: polarisation is most useful when seen in several regions, not in one aligned group of cells.

• Tubular: often dominant; slit-like lumina; apical nuclei.
• Branching / anastomosing: complex ribbons with low-grade cells; fibromuscular stroma → think ELOC or TSC/mTOR RCC.
• Papillary: short, blunt, abortive papillae into cysts.
• Cystic / microcystic: may resemble MCRNLMP.
• Acinar: some acini lack obvious polarisation.
• Solid / compact: minor; extensive solid growth with a ccRCC vascular network → reconsider.

Diagnostic pearl: despite its name, CCPRCT may be predominantly tubular, acinar or cystic rather than papillary.

• Low-grade clear cells: minimal pleomorphism; formal grading generally unnecessary.
• Apical nuclei: a linear band in the luminal half of the epithelium.
• Variable position: not every cell is polarised.
• Focal eosinophilia acceptable; extensive oncocytic cytoplasm → another tumour.
• No high-grade features: pleomorphism, big nucleoli, mitoses or sarcomatoid change require exclusion of carcinoma with CCPRCT-like areas.

Diagnostic pearl: apical alignment is highly useful but not specific, ccRCC can show it focally.

• Fibrous / hyalinised stroma: sometimes with sparse epithelium.
• Smooth muscle-rich stroma: historically “renal angiomyoadenomatous tumour”; part of the CCPRCT spectrum when the epithelium fits, but also seen in ELOC and TSC/mTOR RCC.
• Myxoid / oedematous stroma: unusual low-power look.
• Predominantly cystic or hyalinised: >95% in some cases (2015 series); assess the residual epithelium.
• Perinephric extension: exceptional; review thoroughly for mimics.

Diagnostic pearl: fibromuscular stroma neither establishes ELOC-mutated RCC nor excludes CCPRCT.

• CK7: strong, diffuse · essential; also in ELOC and TSC/mTOR RCC, occasionally ccRCC.
• CAIX: basolateral cup-like membranous (luminal membrane spared) · ccRCC is box-like.
• GATA3: frequently nuclear positive (19/25, 76%) · negativity does not exclude.
• 34βE12: frequently positive · overlaps with TSC/mTOR RCC.
• CD10: negative or focal · diffuse membranous → ccRCC.
• AMACR: usually negative · against PRCC.

Diagnostic pearl: diffuse CK7 + cup-like CAIX first; GATA3 and 34βE12 second line, interpreted with morphology.

• VHL: generally no biallelic inactivation or 3p loss; recent work questions whether any VHL change excludes CCPRCT.
• Chromosomes: simple profile; no 3p loss, no 7/17 gains; nothing diagnostic.
• No defining driver: diagnosis rests on morphology and IHC.
• Mimics: ELOC mutation (± chromosome 8 changes) in ELOC-mutated RCC; TSC1/TSC2/MTOR in TSC/mTOR RCC.

Diagnostic pearl: a driver typical of another RCC should prompt reassessment.

• Architecture: tubular/tubulopapillary/cystic vs nested/alveolar/solid.
• Nuclei: apical, uniformly low grade vs central, variable grade (focal apical possible).
• CK7: diffuse vs negative/focal (occasionally diffuse).
• CAIX: cup-like vs box-like.
• GATA3 / 34βE12: often positive vs usually negative.
• CD10: negative/limited vs often positive.
• Molecular: no biallelic VHL vs VHL/3p.

A 2024 study showed carcinomas can reproduce CCPRCT morphology and CK7/CAIX; some had high-grade nuclei or alternative molecular alterations.

Diagnostic pearl: the main danger is calling a carcinoma CCPRCT because only its CCPRCT-like component was sampled.

ELOC-mutated RCC

• Clear cells in tubules/acini/nests separated by thick fibromuscular bands; CK7 and CAIX overlap (cup-like possible).
• GATA3 and 34βE12 less consistent; a pathogenic ELOC alteration is required.
• 2025: cystic architecture in 15/17 ELOC tumours.

TSC/mTOR RCC with fibromyomatous stroma

• Low-grade clear cells in branching tubules with fibromyomatous stroma; CK7, CAIX, GATA3 and 34βE12 may all be positive.
• Strong diffuse GPNMB (6/6 vs 0/7 CCPRCT, 2023) and nuclear pseudoinclusions favour it; TSC1/TSC2/MTOR.

Diagnostic pearl: in an ambiguous CK7+/CAIX+ tumour with fibromuscular stroma, ELOC or TSC/mTOR testing beats a bigger IHC panel.

• MCRNLMP: entirely cystic with septal clusters; box-like CAIX, VHL background.
• PRCC with clear cell change: foamy macrophages, psammoma bodies; CK7 and AMACR+; no cup-like CAIX or apical row.
• TFE3-rearranged RCC: can mimic CCPRCT; psammoma bodies, hyaline material; molecular testing.
• ccRCC with smooth muscle stroma: conventional areas, box-like CAIX, CD10, VHL/3p.

Diagnostic pearl: clear cells, low grade, CK7 and fibromuscular stroma coexist in several tumours, none is diagnostic alone.

• 1 · Architecture & polarity: tubules, cysts, abortive papillae with luminal nuclei.
• 2 · Exclude incompatible features: ccRCC nests, solid growth, high grade, necrosis.
• 3 · CK7 & CAIX: diffuse CK7, cup-like CAIX.
• 4 · Mimics: GATA3/34βE12+ supports CCPRCT · CD10 diffuse/box-like CAIX → ccRCC · strong GPNMB → TSC/mTOR · fibromuscular + ambiguous → ELOC or TSC/mTOR.
• 5 · Molecular: VHL, ELOC, TSC/mTOR when unresolved.

• Diagnosable on core when morphology and immunophenotype are convincing.
• Sampling may miss a ccRCC component or a molecular mimic.
• High-grade nuclei or discordant staining → reconsider.
• When ambiguous: “low-grade renal neoplasm with clear cell papillary features”.

2025 biopsy study: of 25 resected, 18 confirmed CCPRCT and 7 were alternatives (5 RCC with fibromyomatous stroma, 1 ccRCC, 1 MCRNLMP); 16/19 biopsies favouring CCPRCT (84%) were concordant. Confirmed CCPRCTs: CK7 and cup-like CAIX 18/18, GATA3 11/14, 34βE12 16/16, CD10 negative 16/17.

• CCPRCT-like ≠ indolent: 2024: 15 tumours with CCPRCT-like features included ccRCC, a TFE3-associated tumour and a TSC-altered tumour.
• VHL boundary: 2026 AJSP: of 17 original CCPRCTs, 5 were reclassified as ccRCC; 7 VHL wild-type and 5 monoallelic VHL remained, without recurrence, monoallelic change may be compatible.
• GATA3 / 34βE12 not specific: expressed in TSC/mTOR RCC and focally in ELOC tumours (2025).
• GPNMB & pseudoinclusions: point to TSC/mTOR RCC.
• Molecular refinement: confidence should drop when findings are discordant.

• WHO name: clear cell papillary renal cell tumour: indolent.
• Tubular/tubulopapillary; true papillae not mandatory.
• Apical nuclei away from the basement membrane, possibly focal; uniformly low grade.
• Diffuse CK7 + cup-like CAIX (luminal membrane spared).
• GATA3 and 34βE12 often positive, not specific; diffuse CD10 → ccRCC.
• Smooth muscle stroma also in ELOC and TSC/mTOR RCC; strong GPNMB → TSC/mTOR.
• Usually no biallelic VHL; monoallelic VHL may be compatible.
• Atypia, necrosis, sarcomatoid change or a conventional RCC component → reconsider.